Veterans suffer at a disproportional rate from squamous cell carcinoma of the head and neck (SCCHN) due to carcinogen exposure from tobacco and alcohol. Despite aggressive treatments, SCCHN is a devastating disease that portends an overall 5-year survival of only ~50%. A comprehensive genomic analysis of SCCHN revealed that ~30% of these tumors overexpress a gene that encodes a calcium-activated chloride channel (TMEM16A/ ANO1). Mechanistic studies have shown that TMEM16A contributes to tumor cell growth by activating the EGFR-ERK1/2 pathway. EGFR is the only FDA-approved molecular therapeutic target in SCCHN, yet the critical therapeutic biomarker(s) that predict response to anti-EGFR therapy remains unknown. Here, we propose to investigate the how TMEM16A and EGFR interact with each other to promote tumor growth and progression. We propose the following studies: 1) determine whether chloride flux through TMEM16A is necessary and sufficient to activate EGFR signaling; 2) examine how TMEM16A interacts with EGFR, and if this interaction is necessary for tumor cell growth; and 3) use a patient samples and tissues derived from a mouse model of carcinogenesis to determine if TMEM16A expression / TMEM16A-EGFR interaction is required for the development of oral dysplasia and ultimately progression to invasive carcinoma. At the conclusion of this project, we intend to implicate TMEM16A as a direct therapeutic target for the treatment of Veterans with OSCC.